Nicolas Collongues

Aquaporin-4 antibody–negative neuromyelitis optica Distinct assay sensitivity–dependent entity

Objective: To optimize aquaporin-4 (AQP4) antibody (Ab) detection and to assess the influence of the increased sensitivity of the assay on the demographic and disease-related characteristics of a group of AQP4-Ab–negative patients. Methods: Serum samples were obtained from patients included in the French NOMADMUS database with a definite diagnosis of neuromyelitis optica (NMO) (n = 87) and were compared with controls (n = 54). They were tested by indirect immunofluorescence and cell-based assays (CBAs) in various conditions and with several plasmids. Results: We identified the CBA on live cells transfected with the untagged AQP4-M23 isoform as the best method, with a sensitivity of 74.4% and a specificity of 100%. We demonstrated a direct relationship between improvement of the sensitivity of the detection method and the distinctiveness and characteristics of the AQP4-Ab–negative NMO group. Whereas with the classic indirect immunofluorescence or current AQP4-M1 CBA we found only slight differences between the 2 populations, using the AQP4-M23 CBA, we demonstrated that patients with AQP4-Ab–negative NMO expressed specific demographic and disease-related features. They were characterized by an equal male/female ratio (p < 0.001), a Caucasian ethnicity (p = 0.029), and an overrepresentation of simultaneous optic neuritis and transverse myelitis at first episode (p = 0.015). In terms of disability, they experienced a better visual acuity at last follow-up compared with seropositive NMO (p = 0.007). Conclusion: This raises the question of a distinct physiopathology for patients with AQP4-Ab–negative NMO and of their place in the spectrum of the disease.

Current and future treatment approaches for neuromyelitis optica

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) characterized by severe attacks of optic neuritis and myelitis, and which, unlike multiple sclerosis (MS), commonly spares the brain in the early stages. NMO used to be considered as a special form of MS. During the past 10 years, however, the two diseases have been shown to be clearly different. NMO is a B-cell-mediated disease associated with anti-aquaporin-4 antibodies in many cases and its pathophysiology seems to be near the acute lesion of necrotizing vasculitis. Assessment of prevalence shows that NMO is far less frequent than MS, which explains the absence of randomized clinical trials and NMO treatment strategies validated by evidence-based medicine. Recently, many data have been published that suggest that the therapeutic option in NMO should be immunosuppressive rather than immunomodulatory drugs. In the present study, after a brief overview of NMO, we review therapeutic studies and propose new therapeutic strategies in the relapse and disease-modifying fields.

White Matter Atrophy and Cognitive Dysfunctions in Neuromyelitis Optica

Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system characterized by optic neuritis and longitudinally extensive acute transverse myelitis. NMO patients have cognitive dysfunctions but other clinical symptoms of brain origin are rare. In the present study, we aimed to investigate cognitive functions and brain volume in NMO. The study population consisted of 28 patients with NMO and 28 healthy control subjects matched for age, sex and educational level. We applied a French translation of the Brief Repeatable Battery (BRB-N) to the NMO patients. Using SIENAx for global brain volume (Grey Matter, GM; White Matter, WM; and whole brain) and VBM for focal brain volume (GM and WM), NMO patients and controls were compared. Voxel-level correlations between diminished brain concentration and cognitive performance for each tests were performed. Focal and global brain volume of NMO patients with and without cognitive impairment were also compared. Fifteen NMO patients (54%) had cognitive impairment with memory, executive function, attention and speed of information processing deficits. Global and focal brain atrophy of WM but not Grey Matter (GM) was found in the NMO patients group. The focal WM atrophy included the optic chiasm, pons, cerebellum, the corpus callosum and parts of the frontal, temporal and parietal lobes, including superior longitudinal fascicle. Visual memory, verbal memory, speed of information processing, short-term memory and executive functions were correlated to focal WM volumes. The comparison of patients with, to patients without cognitive impairment showed a clear decrease of global and focal WM, including brainstem, corticospinal tracts, corpus callosum but also superior and inferior longitudinal fascicles. Cognitive impairment in NMO patients is correlated to the decreased of global and focal WM volume of the brain. Further studies are needed to better understand the precise origin of cognitive impairment in NMO patients, particularly in the WM.

JC-virus seroconversion in multiple sclerosis patients receiving natalizumab:

Aim: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. Methods: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. Results: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. Conclusion: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

Rituximab in refractory and non-refractory myasthenia: a retrospective multicenter study.

Few data are available about the effect of rituximab (RTX) on refractory (RM) and non‐refractory (NRM) myasthenia.

A Benign Form of Neuromyelitis Optica: Does It Exist?

BACKGROUND Few data exist on a possible benign form of neuromyelitis optica (NMO). OBJECTIVES To identify NMO with a good outcome (go-NMO) among a large population of patients and to describe demographic and clinical variables associated with go-NMO vs standard NMO and benign multiple sclerosis. DESIGN Observational retrospective multicenter study. SETTING Twenty-five medical centers in metropolitan France (MF) and 3 medical centers in the French West Indies (FWI). PATIENTS A total of 175 patients with NMO were retrospectively analyzed from 2 cohorts: 125 in MF and 50 patients of nonwhite race/ethnicity in the FWI. Patients in MF fulfilled the 2006 NMO criteria, whereas patients in the FWI fulfilled the 1999 or 2006 NMO criteria. Neuromyelitis optica and multiple sclerosis databases were reviewed, and patients with a score of 3 or lower on the Expanded Disability Status Scale after a 10-year follow-up period were considered to have go-NMO. MAIN OUTCOME MEASURES Clinical, laboratory, and magnetic resonance imaging data and course of disability. RESULTS In MF, go-NMO was observed in 11 patients, including 3 untreated patients. In the FWI, NMO was severe because of disability related to optic neuritis. Compared with standard NMO, go-NMO was associated with a lower annualized relapse rate (0.3 vs 1.0, P < .01), and 8 of 11 patients with go-NMO showed complete regression of myelitis on magnetic resonance imaging during the disease course. Three patients experienced a disabling attack of NMO after 15 years of follow-up. A good outcome occurred less frequently among patients with NMO than among patients with multiple sclerosis (12.0% vs 22.4%, P = .03). CONCLUSIONS Among patients in MF, go-NMO occurs rarely. However, because a disabling attack may occur after a long follow-up period, a benign form of NMO cannot be defined.

Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset

Background: Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). Objective: To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. Methods: We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. Results: We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. Conclusion: LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.

White matter volume is decreased in the brain of patients with neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory disease involving predominantly the spinal cord and optic nerves. Whether patients with NMO have a loss in white or grey matter (GM) volumes remains to be determined.

Reduction of the washout time between natalizumab and fingolimod

Drugs such as natalizumab (Tysabri) and fingolimod (Gilenya) are now available to treat multiple sclerosis (MS) and are usually proposed for patients with active MS. Several studies recently reported that the disease was frequently reactivated between 3 and 6 months after the withdrawal of Tysabri treatment.1–2 These results suggest the need for a therapeutic alternative that can be quickly introduced if Tysabri has to be withdrawn. However, there are also recommendations for a delay of 3 months between two immunosuppressive drugs. We extracted clinical data from the all patients in our region (Alsace, France) who had received at least one month of Gilenya treatment (n=164) between the 1 January 2012 and 1 January 2013. Some 59 patients in this cohort (36%) had switched from Tysabri to Gilenya, mainly due to positive JC virus serology (96.6%). All patients had stopped Tysabri at least 6 months before the time of data analysis, thus allowing us to evaluate the high-risk period (3–6 months) for MS reactivation. We then compared the subgroup of patients with and the subgroup of patients without relapses in terms of the mean delay between stopping Tysabri and starting Gilenya. We also compared the frequency of relapses in patients treated with Gilenya less than 3 months after stopping Tysabri and those treated 3 months or more after. The mean time on Gilenya treatment was 7 months (range: 1–12 months). All patients but three (94.9%) were treated with Gilenya for 6 months or more and were still receiving the treatment at the end of the study. Of the three patients who stopped Gilenya, one stopped because of disease reactivation (three relapses in 5 months) and two stopped because of side effects (gastro-intestinal symptoms) after 1 month. We did not find any differences between the two subgroups regarding age, sex ratio, Expanded Disability Status Scale (EDSS) score or disease duration. Eleven patients (18.6%) had at least one relapse. We observed eight patients (50%) with at least one relapse in the subgroup treated with Gilenya after a delay of 3 months or more (n=16) but only three patients (7%) in the group treated after a delay of less than 3 months (n=43) (p=0.02). The mean delay between the two drugs was 1.7 months (±0.55) for the whole cohort. However, in the subgroup without relapses the mean delay was 1.3 months (±0.32) versus 3.3 months (±1.1) in the group with relapses (p<0.05). Our results clearly argue in favour of an early switch between Tysabri and Gilenya instead of applying the classical washout period of 3 months or more. These results are in accordance with the recent studies showing frequent relapses in patients treated with Gilenya after a delay of 3 months or more.3–5 We recommend reducing as much as possible the delay between the withdrawal of natalizumab and the introduction of fingolimod, to reduce the likelihood of a reactivation of the disease during this high-risk period. One month could be a suitable delay, but this proposition will need to be confirmed in larger studies.

Neuromyelitis optica spectrum disorders in children and adolescents

Neuromyelitis optica (NMO) is a severe autoimmune disease of the CNS characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. NMO is infrequent in children, but early recognition is important to start adequate treatment. In this article, we review the evolving diagnostic criteria of NMO and provide an update on the clinical and neuroimaging spectrum of the disorder in pediatric patients, including current knowledge on immunopathogenesis and treatment recommendations for children with NMO.